Prostanoic acid derivatives as agents for lowering intraocular pressure

ABSTRACT

The present invention provides a method of treating ocular hypertension or glaucoma which comprises administering to an animal having ocular hypertension or glaucoma therapeutically effective amount of a compound represented by the general formula I;                    
     wherein hatched lines represent the α configuration, a triangle represents the β configuration and a dotted line represents the presence or absence of a double bond; 
     A and B are CH 2 ; 
     D represents a covalent bond or CH 2 , O, S or NH; 
     X is CO 2 R, CONR 2 , CH 2 OR, P(O)(OR) 2 , CONRSO 2 R SONR 2  or                    
     Y is O, OH, OCOR 2 , halogen or cyano; 
     Z is CH 2  or a covalent bond; 
     R is H or R 2 ; 
     R 1  is H, R 2 , phenyl, or COR 2 ; 
     R 2  is C 1 -C 5  lower alkyl or alkenyl and R 3  is benzothienyl, benzofuranyl, naphthyl or substituted derivatives thereof, wherein the substituents maybe selected from the group consisting of C 1 -C 5  alkyl, halogen, CF 3 , CN, NO 2 , NR 2 , CO 2 R and OR.

FIELD OF THE INVENTION

The present invention relates to prostanoic acid derivatives as potentocular hypotensives that are particularly suited for the management ofglaucoma.

BACKGROUND OF THE INVENTION Description of Related Art

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical b-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives have been reported to possessocular hypotensive activity, and have been recommended for use inglaucoma management. Eicosanoids and derivatives include numerousbiologically important compounds such as prostaglandins and theirderivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2β))].

Prostaglandins were earlier regarded as potent ocular hypertensives,however, evidence accumulated in the last decade shows that someprostaglandins are highly effective ocular hypotensive agents, and areideally suited for the long-term medical management of glaucoma (see,for example, Bito, L. Z. Biological Protection with Prostaglandins,Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252;and Bito, L. Z., Applied Pharmacology in the Medical Treatment ofGlaucomas Drance, S. M. and Neufeld, A. H. eds., New York, Grune &Stratton, 1984, pp. 477-505. Such prostaglandins include PGF_(2α),PGF_(1α), PGE₂, and certain lipid-soluble esters, such as C₁ to C₂ alkylesters, e.g. 1-isopropyl ester, of such compounds.

Although the precise mechanism is not yet known experimental resultsindicate that the prostaglandin-induced reduction in intraocularpressure results from increased uveoscleral outflow [Nilsson et.al.,Invest. Ophthalmol. Vis. Sci. (suppl), 284 (1987)].

The isopropyl ester of PGF_(2α) has been shown to have significantlygreater hypotensive potency than the parent compound, presumably as aresult of its more effective penetration through the cornea. In 1987,this compound was described as “the most potent ocular hypotensive agentever reported” [see, for example, Bito, L. Z., Arch. Ophthalmol. 105,1036 (1987), and Siebold et.al., Prodrug 53 (1989)].

Whereas prostaglandins appear to be devoid of significant intraocularside effects, ocular surface (conjunctival) hyperemia and foreign-bodysensation have been consistently associated with the topical ocular useof such compounds, in particular PGF_(2α) and its prodrugs, e.g., its1-isopropyl ester, in humans. The clinical potentials of prostaglandinsin the management of conditions associated with increased ocularpressure, e.g. glaucoma are greatly limited by these side effects.

In a series of co-pending United States patent applications assigned toAllergan, Inc. prostaglandin esters with increased ocular hypotensiveactivity accompanied with no or substantially reduced side-effects aredisclosed. The co-pending U.S. Ser. No. 596,430 (filed Oct. 10, 1990,now U.S. Pat. No. 5,446,041), relates to certain 11-acyl-prostaglandins,such as 11-pivaloyl, 11-acetyl, 11-isobutyryl, 11-valeryl, and11-isovaleryl PGF_(2α). Intraocular pressure reducing 15-acylprostaglandins are disclosed in the co-pending application U.S. Ser. No.175,476 (filed Dec. 29, 1993). Similarly, 11,15-9,15 and 9,11-diestersof prostaglandins, for example 11,15-dipivaloyl PGF_(2α) are known tohave ocular hypotensive activity. See the co-pending patent applicationsU.S. Ser. No. 385,645 (filed Jul. 7, 1989, now U.S. Pat. No. 4,994,274),Ser. No. 584,370 (filed Sep. 18, 1990, now U.S. Pat. No. 5,028,624) andSer. No. 585,284 (filed Sep. 18, 1990, now U.S. Pat. No. 5,034,413). Thedisclosures of all of these patent applications are hereby expresslyincorporated by reference.

SUMMARY OF THE INVENTION

The present invention concerns a method of treating ocular hypertensionwhich comprises administering to a mammal having ocular hypertension atherapeutically effective amount of a compound of formula I

wherein hatched lines represent the α configuration, a trianglerepresents the β configuration, a wavy line represents either the αconfiguration or the β configuration, and a dotted line represents thepresence or absence of a double bond;

A and B are CH₂;

D represents a covalent bond or CH₂, O, S or NH;

X is CO₂R, CONR₂, CH₂OR, P(O)(OR)₂, CONRSO₂R, SONR₂ or

Y is O, OH, OCOR², halogen or cyano;

Z is CH₂ or a covalent bond;

R is H or R²;

R¹ is H, R², phenyl, or COR₂;

R² is C₁-C₅ lower alkyl or alkenyl and R³ is benzothienyl, benzofuranyl,naphthyl, or substituted derivatives thereof, wherein the substituentsmaybe selected from the group consisting of C₁-C₅ alkyl, halogen, CF₃,CN, NO₂, NR₂, CO₂R and OR.

In a still further aspect, the present invention relates to apharmaceutical product, comprising

a container adapted to dispense its contents in a metered form; and

an ophthalmic solution therein, as hereinabove defined.

Finally, certain of the compounds represented by the above formula,disclosed below and utilized in the method of the present invention arenovel and unobvious.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIG. 1 is a schematic of the chemical synthesis of a certain compoundsof the invention as disclosed in Examples 1 and 2.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of prostanoic acid derivativesas ocular hypotensives. The compounds used in accordance with thepresent invention are encompassed by the following structural formula I:

A preferred group of the compounds of the present invention includescompounds that have the following structural formula II:

Another preferred group includes compounds having the formula III:

In the above formulae, the substituents and symbols are as hereinabovedefined.

In the above formulae:

Preferably D represents a covalent bond or is CH₂; more preferably D isCH₂.

Preferably Z represents a covalent bond.

Preferably R is H.

Preferably R¹ is H.

Preferably Y═O.

Preferably X is CO₂R and more preferably R is selected from the groupconsisting of H, methyl, i-propyl and n-propenyl.

The above compounds of the present invention may be prepared by methodsthat are known in the art or according to the working examples below.The compounds, below, are especially preferred representative, of thecompounds of the present invention.

(Z)-7-{(1R,2R,3R)-2-[(E)-(S)-5-(3-Chlorobenzo[b]thiophen-2-yl)-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicacid allyl ester (6a)

(Z)-7-{(1R,2R,3R)-2-[(E)-(S)-5-(3-Chlorobenzo[b]thiophen-2-yl)-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicacid (7a)

(Z)-7-{(1R,2R,3R)-2-((E)-(S)-5-Benzo[b]thiophen-2-yl-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicacid allyl ester (6b)

(Z)-7-{(1R,2R,3R)-2-((E)-(S)-5-Benzo[b]thiophen-2-yl-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicacid (7b)

(Z)-7-{(1R,2R,3R)-3-Hydroxy-2-((E)-(S)-3-hydroxy-5-naphthalen-2-yl-pent-1-enyl)-5-oxocyclopentyl}hept-5-enoicacid allyl ester (6c)

(Z)-7-{(1R,2R,3R)-3-Hydroxy-2-((E)-(S)-3-hydroxy-5-naphthalen-2-yl-pent-1-enyl)-5-oxocyclopentyl}hept-5-enoicacid (7c)

(Z)-7-{(1R,2R,3R)-2-[(E)-(S)-5-(4-Bromo-2,5-dimethylthiophen-3-yl)-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicacid allyl ester 6d)

(Z)-7-{(1R,2R,3R)-2-[(E)-(S)-5-(4-Bromo-2,5-dimethylthiophen-3-yl)-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicacid (7d)

Pharmaceutical compositions may be prepared by combining atherapeutically effective amount of at least one compound according tothe present invention, or a pharmaceutically acceptable acid additionsalt thereof as an active ingredient, with conventional ophthalmicallyacceptable pharmaceutical excipients, and by preparation of unit dosageforms suitable for topical ocular use. The therapeutically efficientamount typically is between about 0.0001 and about 5% (w/v), preferablyabout 0.001 to about 1.0% (w/v) in liquid formulations.

For ophthalmic application, preferably solutions are prepared using aphysiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 6.5 and 7.2with an appropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. The preferred chelating agent isedentate disodium, although other chelating agents may also be used inplace or in conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative  0-0.10 vehicle   0-40 tonicity adjustor   1-10 buffer 0.01-10 pHadjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as neededpurified water as needed to make 100%

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The ophthalmic formulations of the present invention are convenientlypackaged in forms suitable for metered application, such as incontainers equipped with a dropper, to facilitate the application to theeye. Containers suitable for dropwise application are usually made ofsuitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution.

The invention is further illustrated by the following non-limitingExamples, which are summarized in the reaction schemes of figures 1through 3 wherein the compounds are identified by the same designator inboth the Examples and the Figures.

EXAMPLE 1(Z)-7-{(1R,2R,3R,5S)-2-[(E)-(S)-5-(3-Chlorobenzo[b]thiophen-2-yl)-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicAcid Allyl Ester (6a)

Step 1: Preparation of Enone (2a)

To a suspension of sodium hydride (39 mg, 1.7 mmol) in tetrahydrofuran(THF) (3.1 mL) cooled to 0 ° C. was added[4-(3-chlorobenzo[b]thiophen-2-yl)-2-oxobutyl]phosphonic acid dimethylester (536 mg, 1.7 mmol) in THF (2.0 mL). After 15 minutes a solution ofaldehyde 1 (750 mg, 1.54 mmol) in THF (3.0 mL) was added and thereaction solution was allowed to slowly warm to 23° C. over a period of16 h. The reaction was quenched with saturated aqueous NH₄Cl andextracted with ethylacetate (EtOAc). The combined organics were washedwith brine, dried over MgSO₄, filtered and concentrated in vacuo.Purification of the residue by flash column chromatography (FCC) (silicagel, 3:2 hexane/EtOAc) provided 1.0 g (98%) of enone 2a.

Step 2: Preparation of α-alcohol (3a)

Sodium tetrahydridoborate (57 mg, 1.51 mmol) was added to a solution ofenone 2a in MeOH (3.1 mL) at 0° C. After 4 h the solvent was removed invacuo and the residue was partitioned between saturated aqueous ammoniumchloride and CH₂Cl₂. The organic portion was separated, dried (Na₂SO₄),filtered and concentrated in vacuo. Purification of the residue by flashcolumn chromatography (silica gel, 3:2 hexane/EtOAc) afforded 500 mg(50%) of pure α-alcohol 3a.

Step 3: Preparation of Allyl Ester (4a)

Lithium hydroxide (3.5 mL of a 0.5N solution in H₂O, 1.74 mmol) wasadded to a solution of the ester 3a (500 mg, 0.76 mmol) in THF (7.0 mL)at 23° C. After 16 h the reaction mixture was acidified with 1N HCl andextracted with EtOAc. The organic portion was washed twice with brine,dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography (silica gel, 100% EtOAc) toafford 339 mg (70%) of the corresponding free acid.

A solution of the acid in acetone (1.1 mL) was treated with1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL, 1.57 mmol) followed byallylbromide (0.23 mL, 2.62 mmol) and stirred at 23° C. for 16 h. Thesolvent was removed in vacuo. The residue was diluted with EtOAc andwashed with 1N HCl, saturated aqueous NaHCO₃ and brine. The organicportion was dried (MgSO₄), filtered and concentrated in vacuo.Purication of the residue by flash column chromatography gave 293 mg(81%) of the allyl ester 4a.

Step 4: Preparation of bis-TBDMS Ether (5a)

A solution of bis-THP ether 4a (293 mg, 0.43 mmol) and pyridiniump-toluene sulfonate (129 mg, 0.51 mmol) in MeOH (0.85 mL) was heated at40° C. for 16 h. The solvent was removed in vacuo. The residue wasdiluted with EtOAc and then washed with 1N HCl, saturated aqueousNaHCO₃, and brine. The organic portion was dried over MgSO₄, filteredand concentrated in vacuo. Purification of the residue by flashchromatography (silica gel, 100% EtOAc) gave 217 mg (98%) of thecorresponding trihydroxy-ester.

A solution of the trihydroxy-ester, TBDMSCl (129 mg, 0.86 mmol),4-dimethylaminopyridine (12.8 mg, 0.10 mmol) and Et₃N (0.18 mL, 1.25mmol) in CH₂Cl₂ (0.84 mL) was stirred for 16 h. The reaction was dilutedwith EtOAc and washed with 1N HCl, saturated aqueous NaHCO₃, and brine.The organic portion was dried over MgSO₄, filtered and concentrated invacuo. Purification of the residue by flash chromatography (silica gel,4:1 hex/EtOAc) gave 178 mg (57%) of the bis-TBDMS ether 5a.

Step 5: Oxidation and Deprotection of (5a)

Tetrapropylammonium perruthenate (4.2 mg, 0.012 mmol) was added to amixture of alcohol 5a (178 mg, 0.24 mmol), 4-methylmorpholine N-oxide(42 mg, 0.36 mmol) and crushed 4A sieves (10 mg) in CH2Cl2 (0.5 mL) at23° C. After 4 h the reaction was concentrated in vacuo and the residuewas purified by flash column chromatography (silica gel, 4:1 hex/EtOAc)to afford 160 mg (90%) of the corresponding 9-keto ester.

The 9-keto ester was deprotected with hydrogen fluoride-pyridine (0.23mL) in CH₃CN (7.2 mL) for 18 h. The reaction was neutralized with NaHCO₃and extracted with EtOAc. The organic portion was washed with brine,dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by flash column chromatography (silica gel, 3:1 hex/EtOAc) toyield 94 mg (85%) of allyl ester 6a.

EXAMPLE 2(Z)-7-{(1R,2R,3R,5S)-2-[(E)-(S)-5-(3-Chlorobenzo[b]thiophen-2-yl)-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicAcid (7a)

Pyrrolidine (15 mL, 0.178 mmol) was added to a solution of allyl ester7a (46 mg, 0.089 mmol) and tetrakis(triphenylphosphine)palladium(0)(10.3 mg, 0.009 mmol) in CH₂Cl₂ (0.2 mL) at 23° C. After 4 h thereaction was diluted with EtOAc and washed with 1N HCl then brine. Theorganic portion was dried (MgSO₄), filtered and concentrated in vacuo.Purification of the residue by flash column chromatography (silica gel,9:1 CH₂Cl₂/MeOH) gave 10 mg (24%) of the above titled compound.

The effects of the compounds of this invention on intraocular pressureare also measured. The compounds are prepared at the said concentrationsin a vehicle comprising 0.1% polysorbate 80 and 10 mM TRIS base. Dogsare treated by administering 25 μl to the ocular surface, thecontralateral eye received vehicle as a control. Intraocular pressure ismeasured by applanation pneumatonometry. Dog intraocular pressure ismeasured immediately before drug administration and at 6 hoursthereafter.

Compounds 6(a) and 7(a) are examined and show a pronounced ocularhypotensive effect in dogs and the glaucomatous cynomonlgus monkeys,respectively.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof,rather, the ambit of the present invention is to be governed only by thelawful construction of the appended claims.

What is claimed is:
 1. A method of treating ocular hypertension orglaucoma which comprises administering to an animal having ocularhypertension or glaucoma a compound selected from the group consistingof(Z)-7-{(1R,2R,3R)-2-[(E)-(S)-5-(3-Chlorobenzo[b]thiophen-2-yl)-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicacid allyl ester (6a)(Z)-7-{(1R,2R,3R)-2-[(E)-(S)-5-(3-Chlorobenzo[b]thiophen-2-yl)-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicacid (7a)(Z)-7-{(1R,2R,3R)-2-((E)-(S)-5-Benzo[b]thiophen-2-yl-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicacid allyl ester (6b) (Z)-7-{(1R,2R,3R)2-((E)-(S)-5-Benzo[b]thiophen-2-yl-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicacid (7b)(Z)-7-{(1R,2R,3R)-3-Hydroxy-2-((E)-(S)-3-hydroxy-5-naphthalen-2-yl-pent-1-enyl)-5-oxocyclopentyl}hept-5-enoicacid allyl ester (6c)(Z)-7-{(1R,2R,3R)-3-Hydroxy-2-((E)-(S)-3-hydroxy-5-naphthalen-2-yl-pent-1-enyl)-5-oxocyclopentyl}hept-5-enoicacid (7c)(Z)-7-{(1R,2R,3R)-2-[(E)-(S)-5-(4-Bromo-2,5-dimethylthiophen-3-yl)-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicacid allyl ester (6d) and(Z)-7-{(1R,2R,3R)-2-[(E)-(S)-5-(4-Bromo-2,5-dimethylthiophen-3-yl)-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicacid (7d).
 2. An ophthalmic solution comprising a therapeuticallyeffective amount of a compound selected from the group consisting of(Z)-7-{(1R,2R,3R)-2-[(E)-(S)-5-(3-Chlorobenzo[b]thiophen-2-yl)-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicacid allyl ester (6a)(Z)-7-{(1R,2R,3R)-2-[(E)-(S)-5-(3-Chlorobenzo[b]thiophen-2-yl)-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicacid (7a)(Z)-7-{(1R,2R,3R)-2-((E)-(S)-5-Benzo[b]thiophen-2-yl-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicacid allyl ester (6b) (Z)-7-{(1R,2R,3R)2-((E)-(S)-5-Benzo[b]thiophen-2-yl-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicacid (7b)(Z)-7-{(1R,2R,3R)-3-Hydroxy-2-((E)-(S)-3-hydroxy-5-naphthalen-2-yl-pent-1-enyl)-5-oxocyclopentyl}hept-5-enoicacid allyl ester (6c)(Z)-7-{(1R,2R,3R)-3-Hydroxy-2-((E)-(S)-3-hydroxy-5-naphthalen-2-yl-pent-1-enyl)-5-oxocyclopentyl}hept-5-enoicacid (7c)(Z)-7-{(1R,2R,3R)-2-[(E)-(S)-5-(4-Bromo-2,5-dimethylthiophen-3-yl)-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicacid allyl ester (6d) and(Z)-7-{(1R,2R,3R)-2-[(E)-(S)-5-(4-Bromo-2,5-dimethylthiophen-3-yl)-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl}hept-5-enoicacid (7d).
 3. A pharmaceutical product, comprising a container adaptedto dispense the contents of said container in metered form; and anophthalmic solution according to claim 2 in said container.